1. Field of the Invention
The present invention relates to a method for preparing 2-morpholinoisobornane-10-thiol and intermediates formed therein.
2. Description of Related Art
Generally, an enzyme has its specific structural conformation in bioorganisms. In enzymatic catalysis, the enzyme can only recognize and catalyze particular enantiomers having the recognizable chirality among various enantiomers having different chirality. Therefore, catalytic asymmetric carbon-carbon bond forming reactions are very important in order to synthesize pharmaceutical compounds or natural products that are active in enzymatic catalysis.
Enantioselective addition of organozincs to carbonyl compounds, one of the most powerful methods for constructing chiral carbon-carbon bonds, has been widely studied. In the endeavors of the study, a camphor-derived chiral ligand has been developed for the use in catalytic asymmetric reactions, and that is (−)-2-exo-morpholinoisobornane-10-thiol ((−)-MITH). (−)-MITH can be applied in asymmetric reaction for forming chiral carbon-carbon bonds, for example, reactions shown in the following Schemes 1 and 2.


According to the abovementioned schemes, diarylmethanol derivatives can be prepared. For example, chiral diarylmethanol intermediates used in preparation of pharmaceutical compounds like CDP840 and its analogues for the treatment of asthma and chronic obstructive pulmonary disease, orphenadrine, neobenodine, carbinoxamine, and so on, all can be synthesized in a reaction with (−)-MITH as a chiral ligand.
A known method for preparing (−)-MITH accords to the following Scheme 3.

First, the sulfonic acid group in (1S)-(+)-camphorsulfonic acid is reduced into mercapto and then protected with BnBr. The subsequent steps including formation of oxime, reduction to form amine, formation of morpholino, and final use of sodium to remove Bn from S to form mercapto, are necessary to be carried out. Accordingly, the preparation of (−)-MITH contains six steps in total. However, since the final step in the preparation is the use of sodium, this method is dangerous and disadvantageous in mass production.